PROJECT SUMMARY/ABSTRACT The Gastrointestinal Cancers Program (GICP) is a multidisciplinary research program that has 84 members (52 primary, 31 associate, and 1 adjunct) from 26 departments. Scott Kopetz, Anirban Maitra, and Ernest Hawk provide leadership from medical oncology, pathology, and prevention. The program provides a framework for early detection, screening, prevention, and clinical trials and has 3 major themes: 1) Targeted Therapeutics and Drug Development, 2) Prevention and Early Detection, and 3) Immunotherapy and Immunology. Each theme is addressed by a Specific Aim. Aim 1: To integrate development and clinical evaluation of targeted therapeutics with improved understanding of the heterogeneity of common and rare gastrointestinal malignancies; Aim 2: To develop and implement strategies to improve early detection and prevention of gastrointestinal malignancies, including dissemination of existing knowledge and development of novel approaches to improve standard of care; and Aim 3: To develop and translate an increased understanding of the immune repertoire to improve therapeutic interventions for gastrointestinal malignancies, with emphasis on combining current ?off-the-shelf? immune checkpoint inhibitors with targeted therapies, emerging immunomodulatory agents, multivalent peptide vaccines, oncolytic viruses, and adoptive cellular therapies to overcome barriers to immunotherapy. Since the last competitive renewal, total direct-cost funding has increased 157%. This includes annual direct-cost peer- reviewed funding of $9.8M, including 1 P01, 1 U10, and 2 U01s, excluding a GI SPORE that has earned a potentially fundable priority. Of this funding, $5.8M (59%) is from NCI grants. Since the last submission, program members have authored 1533 published papers: 746 (49%) are intra-programmatic collaborations, 529 (35%) are inter-programmatic collaborations, and 859 (56%) are inter-institutional collaborations. Forty-one percent of articles have appeared in journals with IF >5, 14% in journals with IF >10, and 3% in journals with IF >30, including Lancet, Nature, Science, Cell, Lancet Oncol, Nat Genet, Nat Med, Cancer Cell, J Clin Oncol, Cancer Discov, and J Clin Invest. During the last grant period, new standards of care were established on the basis of work led by program members. These include mTOR inhibition for several neuroendocrine indications, PD-1 inhibition for anal cancer, BRAF and EGFR inhibition for BRAFmut colorectal cancer (CRC), and PD-1 inhibition with nivolumab and ipilimumab for microsatellite instability-high CRC. GICP members described the consensus molecular subtypes of CRC and are in the process of using these subtypes to select patients for future clinical trials/precision therapy strategies. Impactful preclinical work expanded on key concepts of collateral lethality, for example, targeting metabolic gene malic enzyme 2 in SMAD4-deleted pancreatic ductal adenocarcinoma. GICP members use 14 shared resources. Program research has led to strategic alliance agreements with Merck, Ionis Pharmaceuticals, EMD Serono, and MedImmune. CTEP, SWOG, and Early Detection Research Network collaborative efforts have led to leadership and accrual to NCI-supported trials.